The dominant spinocerebellar ataxias (SCA) are a growing group of heterogeneous neurodegenerative diseases with phenotypes consisting of cerebellar ataxia with or without extrapyramidal signs, dysarthria, occulomotor abnormalities, upper and lower motor neuron signs, cognitive decline, epilepsy, autonomic dysfunction, sensory deficits, and psychiatric manifestations. (Pulst S M, ed. Genetics of Movement Disorders. Academic Press, San Diego 2002; Schöls L, Bauer P, Schmidt T, Schulte T, Riess O. Autosomal dominant cerebellar ataxias: clinical features, genetics, and pathogenesis. Lancet Neurol 2004; (5):291-304.) A total of twenty-six loci are known, and for ten SCAs the causative gene or mutation has been determined. The majority of these are represented by abnormal CAG repeat expansions.
Despite the remarkable progress in identifying loci and genes for the dominant ataxias, approximately 40% of SCAs remain unaccounted for. Clinical characterization of the dominant SCAs is difficult, given both the degree of intra- and interfamilial variability and phenotypic similarity seen in mutations of different genes. (Mantuano E, Veneziano L, Jodice C, Frontali M. Spinocerebellar ataxia type 6 and episodic ataxia type 2: differences and similarities between two allelic disorders. Cytogenet Genome Res 2003; 100(1-4):147-153; Gomez C M, Subramony S H. Dominantly inherited ataxias. Semin Pediatr Neurol 2003; 10(3):210-212.) Even for ataxias which share polyglutamine repeat expansions, in vivo and in vitro experiments have revealed remarkable differences in disease pathogenesis. (Ranum L P, Day J W. Myotonic dystrophy: RNA pathogenesis comes into focus. Am J Hum Genet 2004; 74(5):793-804; Lieberman A P, Fischbeck K H, Triplet repeat expansion in neuromuscular disease. Muscle Nerve 2000; 23(6):843-50; Michalik A, Van Broeckhoven C. (2003) Pathogenesis of polyglutamine disorders: aggregation revisited. Hum Mol Genet 2003; 12(2):173-186.) The identification of mutations causing neurodevelopmental and neurodegenerative diseases and the elucidation of the molecular mechanisms by which they cause disease thus represents a major advance in the diagnosis and treatment of neurodegenerative and neurodevelopmental diseases.